Osteopetrosis is a bone disease characterized by a generalized increase in skeletal mass. It is inherited in a number of mammalian species including man and results from a congenital defect in the production or function of specialized bone cells known as osteoclasts. Impairment of osteoclastic activity prevents bone marrow cavity formation resulting in compromised hematologic and neurologic function, lack of or delayed tooth eruption, and abnormally shaped bones. Osteopetrosis is heterogeneous in its phenotypic expression and response to curative therapies. Currently, bone marrow transplantation is the only method known for curing this disease in man and animal. However, not all of the children and similarly, not all of the osteopetrotic mutations, are cured by this procedure. The toothless (tl) rat is a unique osteopetrotic animal model. It is resistant-to-cure by bone marrow transplantation and also has skeletal features characteristic of rickets. Rickets has been frequently associated with osteopetrosis in man, but like the disorder in the tl rat, it is poorly understood. In spite of this reported frequency, none of the patients undergoing bone marrow transplantation for their osteopetrosis have had rickets. The objectives of the proposed research are to increase our understanding of the pathogenesis of osteopetrosis and the associated rickets in tl rats and to determine the role of vitamin D in the etiology of this latter disorder. The results of these studies will provide insights into the future development of procedures to cure the rachitic lesion. Reversal of this lesion will be followed by attempts at curing the osteopetrosis in these animals by bone marrow transplantation to see if this pretreatment has produced a more favorable skeletal environment for engraftment and rescue from this disease. Information from these studies may offer insights into potential therapies for curing other cure-resistant mutations with or without associated rickets and for providing a basis for establishing an appropriate clinical approach to this problem in similarly affected humans.